A particular focus for our laboratory is a family of innate immune receptors known as Nod-like receptors (NLRs). Many of these have the capacity to form intracellular protein complexes called inflammasomes. These biological structures process the pro-inflammatory cytokines IL-1b and IL-18 into their mature forms. Our research has identified substances that activate the inflammasome, and mechanisms by which this inflammation causes disease.

Activation of the inflammasome also triggers an inflammatory form of cell death known as pyroptosis. This programmed form of cell death is a way by which an infected cell can prevent the spread of a micro-organism, but it can also contribute to inflammatory pathology during disease. We are researching the triggers and effectors for this new form of cell death.

This is a particularly exciting time to be working on inflammation because so many new drugs are coming to the clinic. We have the diverse research tools to determine where and why these new drugs can provide benefit.


Selected publications from Prof Seth Masters

Davidson S, Yu CH, Steiner A, Ebstein F, Baker PJ, Jarur-Chamy V, Hrovat Schaale K, Laohamonthonkul P, Kong K, Calleja DJ, Harapas CR, Balka KR, Mitchell J, Jackson JT, Geoghegan ND, Moghaddas F, Rogers KL, Mayer-Barber KD, De Jesus AA, De Nardo D, Kile BT, Sadler AJ, Poli MC, Krüger E, Goldbach Mansky R, Masters SL. Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24. Sci Immunol. 2022 Feb 11;7(68) PMID: 35148201
This publication is available to access: Full text

Steiner A, Reygaerts T, Pontillo A, Ceccherini I, Moecking J, Moghaddas F, Davidson S, Caroli F, Grossi A, Castro FFM, Kalil J, Gohr FN, Schmidt FI, Bartok E, Zillinger T, Hartmann G, Geyer M, Gattorno M, Mendonça LO, Masters SL. Recessive NLRC4-Autoinflammatory Disease Reveals an Ulcerative Colitis Locus. J Clin Immunol. 2022 Feb;42(2):325-335. PMID: 34783940

Moecking J, Laohamonthonkul P, Chalker K, White MJ, Harapas CR, Yu CH, Davidson S, Hrovat-Schaale K, Hu D, Eng C, Huntsman S, Calleja DJ, Horvat JC, Hansbro PM, O’Donoghue RJJ, Ting JP, Burchard EG, Geyer M, Gerlic M, Masters SL. NLRP1 variant M1184V decreases inflammasome activation in the context of DPP9 inhibition and asthma severity. J Allergy Clin Immunol. 2021 Jun;147(6):2134-2145. PMID: 33378691

Yu CH, Davidson S, Harapas CR, Hilton JB, Mlodzianoski MJ, Laohamonthonkul P, Louis C, Low RRJ, Moecking J, De Nardo D, Balka KR, Calleja DJ, Moghaddas F, Ni E, McLean CA, Samson AL, Tyebji S, Tonkin CJ, Bye CR, Turner BJ, Pepin G, Gantier MP, Rogers KL, McArthur K, Crouch PJ, Masters SL. TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS. Cell. 2020 Oct 29;183(3):636-649. PMID: 33031745

Tye H, Yu CH, Simms LA, de Zoete MR, Kim ML, Zakrzewski M, Penington JS, Harapas CR, Souza-Fonseca-Guimaraes F, Wockner LF, Preaudet A, Mielke LA, Wilcox SA, Ogura Y, Corr SC, Kanojia K, Kouremenos KA, De Souza DP, McConville MJ, Flavell RA, Gerlic M, Kile BT, Papenfuss AT, Putoczki TL, Radford-Smith GL, Masters SL. NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease. Nat Commun. 2018 Sep 13;9(1):3728. PMID: 30214011

Moghaddas F, Zeng P, Zhang Y, Schützle H, Brenner S, Hofmann SR, Berner R, Zhao Y, Lu B, Chen X, Zhang L, Cheng S, Winkler S, Lehmberg K, Canna SW, Czabotar PE, Wicks IP, De Nardo D, Hedrich CM, Zeng H, Masters SL. Autoinflammatory mutation in NLRC4 reveals a leucine-rich repeat (LRR)-LRR oligomerization interface. J Allergy Clin Immunol. 2018 Dec;142(6):1956-1967 PMID: 29778503

Murphy AJ, Kraakman MJ, Kammoun HL, Dragoljevic D, Lee MK, Lawlor KE, Wentworth JM, Vasanthakumar A, Gerlic M, Whitehead LW, DiRago L, Cengia L, Lane RM, Metcalf D, Vince JE, Harrison LC, Kallies A, Kile BT, Croker BA, Febbraio MA, Masters SL. IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome. Cell Metab. 2016 Jan 12;23(1):155-64. PMID: 26603191

Masters SL, Lagou V, Jeru I, Baker PJ, Van Eyck L, Parry DA, Lawless D, De Nardo D, Garcia-Perez JE, Dagley LF, Holley CL, Dooley J, Moghaddas F, Pasciuto E, Jeandel PY, Sciot R, Lyras D, Webb AI, Nicholson SE, De Somer L, van Nieuwenhove E, Ruuth-Praz J, Copin B, Cochet E, Medlej-Hashim M, Megarbane A, Schroder K, Savic S, Goris A, Amselem S, Wouters C, Liston A. Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Sci Transl Med. 2016 Mar 30;8(332):332ra45. PMID: 27030597

Kim ML, Chae JJ, Park YH, De Nardo D, Stirzaker RA, Ko HJ, Tye H, Cengia L, DiRago L, Metcalf D, Roberts AW, Kastner DL, Lew AM, Lyras D, Kile BT, Croker BA, Masters SL. Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1beta. J Exp Med. 2015 Jun 1;212(6):927-38. PMID: 26008898

Masters SL, Gerlic M, Metcalf D, Preston S, Pellegrini M, O’Donnell JA, McArthur K, Baldwin TM, Chevrier S, Nowell CJ, Cengia LH, Henley KJ, Collinge JE, Kastner DL, Feigenbaum L, Hilton DJ, Alexander WS, Kile BT, Croker BA. NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity. 2012 Dec 14;37(6):1009-23. PMID: 23219391

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